OBJECTIVE: The effects of preoperative (pre-op) renin-angiotensin system (RAS) inhibitors on outcomes in patients undergoing cardiac surgery remain uncertain. The aim of this study was to evaluate whether the use of pre-op RAS inhibitors affected major outcomes of cardiac surgery. DESIGN: A retrospective cohort study. SETTING: A university teaching hospital. PARTICIPANTS: Patients undergoing cardiac surgery between January 1, 2001 and December 31, 2011. INTERVENTIONS: One thousand two hundred thirty-nine patients who received pre-op RAS inhibitors were compared with those who did not (control group, n = 1,083). MEASUREMENTS AND MAIN RESULTS: Acute kidney injury (AKI) was defined using Acute Kidney Injury Network classification. Patients in the RAS inhibitors group presented with higher comorbidities. Pre-op RAS inhibitors therapy was associated with the reduction in the incidence of AKI (27.2% v 34.0%, p<0.001), septicemia (1.9% v 3.5%, p = 0.019), and operative mortality (2.99% v 4.62%, p = 0.039). After adjusted propensity scores and multivariate logistic regression, the pre-op RAS inhibitors were found to have protective effects against AKI (odds ratio [OR]: 0.764, 95% confidence interval [CI]: 0.670-0.873, p<0.001), septicemia (OR: 0.515, 95% CI: 0.348-0.761, p>0.001), and operative mortality (OR: 0.539, 95% CI: 0.348-0.758, p<0.001). CONCLUSION: The results suggested that pre-op RAS inhibitor therapy was associated with significant reductions in the risk of AKI, operative mortality, and septicemia.